Pseudomonas aeruginosa is a major cause of infection in compromised hosts (1, 2). P. aeruginosa synthesizes a number of extracellular products, including alkaline protease, elastase and toxin A, which are believed to be involved in the pathogenesis of P. aeruginosa infections (3-8). Toxin A, the most toxic of these products, is a potent inhibitor of eucaryotic protein synthesis. The toxin has been shown to catalyze the transfer of the adenosine diphosphate-ribosyl (ADPR) moiety of nicotinamide adenosine dinucleotide (NAD) onto eucaryotic elongation factor 2, thereby rendering this factor nonfunctional in protein synthesis (9-12).
Studies with animal models suggest that toxin A is an important factor in P. aeruginosa infections. In the burned mouse model, toxin A antitoxin therapy provided significant protection when mice were challenged with P. aeruginosa (6). A specific toxin A-deficient mutuant of P. aeruginosa strain PAO-1, termed PAO-T1, exhibited a markedly reduced virulence in a mouse corneal infection model (8) and in the chronic rat lung model. Furthermore, a study of patients with P. aeruginosa bacteremia showed a correlation between a rise in toxin A antibody level and survival (13).
These findings have prompted efforts aimed at developing an efficacious toxin A toxoid vaccine. One approach has been to treat toxin A by chemical means in an attempt to produce a toxoid protein product which is nontoxic, and yet retains its immunogenicity. However, to date these attempts have not been successful in that the chemical treatment either fails to produce an irreversible reduction in the cytotoxicity of the toxin A protein, or the immunogenicity of the protein is severely compromised.